Cellular immune responses play a crucial role in controlling viral replication in HIV-infected individuals. An optimal anti-HIV T cell response is critical for clearing HIV infected cells and central for HIV cure strategies. However, chronic immune activation drives the pathogenesis of HIV-1 infection, leading to loss of CD4+ T cells and exhaustion of antiviral cellular immunity, which is characterized by poor anti-viral responses against HIV. Autophagy, a homeostatic mechanism that involved in the disposal of damaged cellular organelles and elimination intracellular pathogens, is intricately involved in T cell function but it is impaired during HIV infection. In this this study, we will investigate the role of autophagy for HIV immuno-pathogenesis and examine if improving autophagy during chronic HIV infection can restore exhausted anti-viral responses. We will use the humanized mouse model of HIV infection, which mimics HIV immune exhaustion observed in HIV infected patients. We will study the following two aims: 1) Investigate how chronic HIV infection affects T cell autophagy and examine if autophagy inducer treatment can restore/improve exhausted anti-HIV T cells response in vivo. We will examine if inducing autophagy will improve HIV specific T cell autophagy, remodel T cell metabolism, reduce expression of inhibitory receptors and directly improve their functions in vivo.; 2) Investigate the role of autophagy in chronic inflammation during chronic HIV infection and examine if autophagy inducer treatment reduces persistent immune activation, alleviates immune suppression, and indirectly improves anti-viral T cell functions in vivo.
Understanding the immunologic and virologic mechanisms of HIV disease is critical to identify novel targets for therapeutic intervention. Chronic immune activation during HIV infection is highly associated with multiple immunologic dysfunctions and is a strong correlate of disease progression. We will investigate the critical role of autophagy in T cell exhaustion during chronic HIV infection in vivo and develop a novel system to therapeutically target autophagy and chronic immune activation to restore immune competence to fight HIV infection.
